Heterocyclyl 2-(2-(4-hydroxyphenyl)-2-hydroxy-1-methyl)ethylamino)ethyl ketones as lipogenesis inhibitors

ABSTRACT

Certain heterocyclyl 2-(2-(4-hydroxyphenyl)-2-hydroxy-1-methyl)ethylamino)ethyl ketones inhibit lipogenesis in mammals.

DESCRIPTION OF THE INVENTION

It has been found that lipogenesis in mammals is inhibited by certainketones, described by the formula ##STR1## wherein R is hydrogen ormethyl and R¹ is furanyl, benzofuranyl, thienyl, benzothienyl, or any ofthese substituted on the hetero ring by one or two methyl moieties, andtheir physiologically acceptable acid addition salts.

Suitable salts are those of such acids as acetic, succinic, maleic,fumaric, propionic, citric, lactic, pamoic, hydrochloric, sulfuric andphosphoric acids.

Included in the invention are the individual optically active isomers,and diastereomers, as well as mixtures thereof, that inhibitlipogenesis.

The compounds of Formula I are known, being disclosed in U.S. Pat. No.3,803,173.

Compounds of Formula I have been found to inhibit lipogenesis in tissuesof mammals. The manner in which they cause this effect is not known withcertainty; it is believed that they interfere with the synthesis offatty acids in the tissues. Their effectiveness for this purpose hasbeen ascertained by immersing samples of swine adipose tissue in aliquid medium containing radioactive glucose and the test chemical, fora period of time, then isolating the lipid from the treatment tissue anddetermining the incorporation of the radioactive carbon into lipid bymeans of scintillation counting techniques. These tests were conductedin swine adipose tissue because in swine, the primary site oflipogenesis--i.e., fatty acid synthesis--appears to be adipose tissue.

Described in more detail, the tests were conducted according to thefollowing general procedure:

150 milligrams of slices of swine adipose tissue were incubated at 37°C. for 2 hours with shaking in 3 milliliters of Krebs-Ringer bicarbonatesolution containing one-half the normal calcium ion concentration, 60micromoles of glucose, 0.5 micro-Curie of glucose-U¹⁴ C, and 300microunits of insulin, and 5% dimethyl sulfoxide (DMSO). The testcompounds were added as suspensions or solutions in DMSO and werepresent at a concentration of 100 micrograms per milliliter of theincubation mixture.

The incubation was terminated by addition of 0.25 milliliter of 1 Nsulfuric acid. The resulting mixture was extracted with a total of 25milliliters of chloroform:methanol (2:1 v/v). The extracts were washedaccording to Folch et al. (J. Biol. Chem., 226, 497-509, (1957)), airdried, and counted in a liquid scintillation counter with 15 millilitersof counting fluid (two parts toluene containing 0.4% w/v New EnglandNuclear Omnifluor: 1 part Triton X-100). The tests were conducted intriplicate and were accompanied by control tests in which allingredients, proportions and conditions were the same except that notest compound was included. From the data obtained were calculated thepercent inhibition of lipid synthesis by the test compound in each case.

The following individual species of Formula I were tested:

    ______________________________________                                        Compound No. Name                                                             ______________________________________                                        1            1-(2-furanyl)-3-(2-hydroxy-2-(4-                                              hydroxyphenyl)-1-methylethyl-                                                 amino)-1-propanone, hydrochloride.                               2            1-(2,5-dimethyl-3-thienyl)-3-(2-                                              hydroxy-2-(4-hydroxyphenyl)-1-                                                methylethylamino)-1-propanone,                                                hydrochloride.                                                   3            1-(3-benzofuranyl)-3-(2-hydroxy-2-                                            (4-hydroxyphenyl)-1-methylethyl-                                              amino)-1-propanone.                                              4            3-(2-hydroxy-2-(4-hydroxyphenyl)-1-                                           methylethylamino)-1-(3-thienyl)-                                              1-propanone, hydrochloride.                                      ______________________________________                                    

The data obtained from the tests are set out in Table 1, as the percentinhibition of lipogenesis compared to the results obtained in thecontrol tests wherein only the test compound was omitted.

                  TABLE 1                                                         ______________________________________                                        Compound No.   Percent Inhibition                                             ______________________________________                                        1              100                                                            2               89                                                            3              100                                                            4               99                                                            ______________________________________                                    

The ketones of Formula I can be used to control lipogenesis inwarm-blooded animals such as, for example, pets, animals in a zoo,livestock, fur-bearing animals and domestic animals, including, but notlimited to dogs, cats, mink, sheep, goats, swine, cattle, horses, mulesand donkeys. The effect is obtained by administering an effective amountof one or a mixture of two or more of the ketones orally or parenterallyto the animal. They may be administered as such, or as an activeingredient of a conventional pharmaceutical formulation. They may beadministered orally by any convenient means. Thus, they may be orallyadministered as a drench, by intubation, in the animal's food and water,in a food supplement or in a formulation expressly designed foradministration of the drug. Suitable formulations include solutions,suspensions, dispersions, emulsions, tablets, boluses, powders,granules, capsules, syrups and elixirs. For parental administration,they may be in the form of a solution, suspension, dispersion oremulsion. They can be administered in the form of an implant or othercontrolled sustained release formulation. Inert carriers, such as one ormore of water, edible oil, gelatin, lactose, starch, magnesium sterate,talc or vegetable gum can be used. The dosage of the ketone needed toinhibit lipogenesis will depend upon the particular ketone used, and theparticular animal being treated. However, in general, satisfactoryresults are obtained when the ketones are administered in a dosage offrom about 1 to about 400 milligrams per kilogram of the animal's bodyweight. The ketone can be administered in a single dose or in a seriesof doses in the same day, or over a period of days. For any particularanimal, a specific dosage regimen should be adjusted according to theindividual need, the particular ketone(s) used as the inhibitor, and theprofessional judgment of the person administering or supervising theadministration of the inhibitor. It is to be understood that the dosagesset forth herein are exemplary only, and that they do not, to anyextent, limit the scope or practice of the invention.

What is claimed:
 1. A method of inhibiting lipogenesis in a mammal,which comprises administering, to a mammal in need of said treatment,orally or parenterally a lipogenesis inhibiting effective amount of acompound of the formula: ##STR2## wherein R is methyl and R¹ is furanylor benzofuranyl or their physiologically acceptable acid addition salts.